5-96740783-G-C

Variant names:

• chr5-96740783-G-C
• NM_001750.7:c.918G>C
• CAST p.Ser306Ser

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001750.7(CAST):​c.918G>C​(p.Ser306Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. S306S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAST NM_001750.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 0 publications found

Genes affected

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

CAST Gene-Disease associations (from GenCC):

• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

CAST (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.152).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.918G>C	p.Ser306Ser	splice_region synonymous	Exon 13 of 32	NP_001741.4
	CAST	NM_001042441.3		c.861G>C	p.Ser287Ser	splice_region synonymous	Exon 12 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.852G>C	p.Ser284Ser	splice_region synonymous	Exon 12 of 31	NP_001035907.1	P20810-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.918G>C	p.Ser306Ser	splice_region synonymous	Exon 13 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.669G>C	p.Ser223Ser	splice_region synonymous	Exon 11 of 30	ENSP00000339914.3
	CAST	ENST00000309190.9	TSL:1	c.603G>C	p.Ser201Ser	splice_region synonymous	Exon 10 of 29	ENSP00000312523.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.72
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-96076487;